Septic shock is the most severe clinical presentation of sepsis, with a poor prognosis despite intensive therapeutic support and anti-infectious strategy to eradicate the infection foci. The sepsis syndrome is defined as symptoms related to the host response to abnormal presence of micro-organisms or their antigenic fractions. The local infection might spread out for different reasons to the whole body, with a particular activation of blood immune cells controlling the innate immunity during the early phase and activation of the adaptive immunity in a second time. Such an intense immune activation in blood may in turn target organs that were not initially concerned by the initial infection, leading to immune toxicity and dysfunction of these organs. The high mortality rate of septic shock (around 50%) results from a combination of organ failures, comorbidities and virulence of micro-organisms. Death may occur at different times of evolution, most often during the first week despite intensive resuscitation.
A number of studies examining therapeutic interventions have generated important but controversial results, such as the use of corticosteroids (Annane et al., 2002; Sprung et al., 2008), activated protein C (Bernard et al., 2001), and tight glycaemic control (van den Berghe et al., 2001). The absence of an early, specific and sensitive marker for determining prognosis thus creates difficulties not only for clinicians with regard to prescription of expensive drugs and futile maintenance of life support, but also for trial investigators with regard to the selection of patients for study inclusion. Some promising markers have been tested, such as procalcitonin (Clec'h et al., 2004), HLA-DR (Monneret et al., 2006), IL-6 (Abraham et al., 2001), and soluble triggering receptor expressed on myeloid cells-1 (sTREM) (Gibot et al., 2005); but results are conflicting.
Recently, a novel group of molecules—known variously as “endokines”, “alarmins” or “damage-associated molecular pattern proteins (DAMPs)” —that are released by activated or damaged cells under conditions of cell stress has been investigated (Oppenheim et al., 2007). Among these, phagocytic S100 proteins, members of the calgranulin family that mediate inflammatory responses (Vogl et al., 2007) and organ function (Boyd et al., 2008) appear to be of importance in sepsis. An emerging concept of pattern recognition involves the multi-ligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including the S100 proteins (Brunn and Platt, 2006; Foell et al., 2007).
Overexpression of the genes of S100A8 and A9 has been shown in mice submitted to lipopolysaccharide (LPS) or caecal ligation and puncture (CLP) challenge (Vogl et al., 2007), in cardiomyocytes incubated with LPS (Boyd et al., 2008), in kidney tissue after ischaemia/reperfusion (Grigoryev et al., 2008), in healthy volunteer leucocytes after LPS injection (Talwar et al., 2006) and in septic shock patients (Payen et al., 2008). Since S100A8 and S100A9 proteins are found in both intracellular and extracellular spaces, they could potentially act both within the cell and in an autocrine or paracrine manner. In mice with septic shock, there were high levels of both gene expression and the proteins (Vogl et al., 2007). Few studies have examined cellular or extracellular levels of these proteins in human septic shock.